Milder Form of Vici Syndrome Due to Novel Missense Variant in Epg5 Gene Affecting Splicing: A Case Report

Objective. Vici syndrome is a rare neurodevelopmental disorder with multisystem involvement, caused by mutations in the EPG5 gene encoding a protein involved in autophagy. It includes dysgenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, and immuno-deficiency. Here we report a case of a 9-year-old boy of Roma ethnicity with a milder form of Vici syndrome and a novel variant in the EPG5 gene. Methods. DNA and RNA were extracted from the whole blood. Whole exome sequencing was performed and analysed with an in-house bioinformatics pipeline. A mini-gene assay was performed for EPG5 exon 23 with or without the tested variant. Results. The patient was born prematurely and presented with hypotonia, severe hypotrophy and growth retardation, developmental delay, congenital heart defects, mild brain atrophy, and a thin corpus callosum. Whole exome analysis identified a novel variant c.4205G>A, p.(Arg1402Lys) in the EPG5 gene, suggesting the diagnosis of Vici syndrome. Further examination of symptoms commonly associated with Vici syndrome confirmed hypopigmented skin areas and immunodeficiency. No seizures, cataracts, or cardiomyopathy were observed. As the variant is located at the last base of exon 23, we sequenced the patient's EPG5 mRNA and detected aberrant transcripts in addition to correctly spliced ones. The mini-gene assay confirmed decreased inclusion of the mutated exon compared with the wild-type (40% vs. 72%, respectively). Conclusion. Novel variant EPG5:c.4205G>A, p.(Arg1402Lys) causes aberrant splicing only in a small proportion of transcripts; therefore, the milder presentation of Vici syndrome in our patient is probably due to the residual presence of EPG5 protein.